[unreadable] The adipocyte hormone leptin plays a key role in the control of energy balance. We and others have demonstrated a synergistic effect of administered glucocorticoids (GC) and food intake (or insulin) on leptin in lean and obese subjects. Morning food intake produces an increase in insulin, a midday spike of cortisol and an increase of leptin at night. During fasting, neither insulin or cortisol peak in midday, and leptin does not rise at night. Administration of insulin alone cannot produce the meal-entrained nocturnal rise in serum leptin. We hypothesize that the spike of cortisol occurring with feeding is permissive for post-prandial insulin effects on nighttime leptin. Thus we anticipate that administration of metyrapone, a blocker of cortisol production, should blunt the leptin response to food intake. Accordingly, the administration of hydrocortisone to subjects receiving metyrapone, by artificially simulating the midday surge of cortisol, will restore the leptin response to the meal. This mechanistic experiment will be conducted in lean subjects. Obesity, particularly abdominal obesity, is associated with perturbations of the hypothalamic-pituitary-adrenal (HPA) axis. The response of plasma cortisol to stressors, such as a lunch meal, is increased. The leptin response to the administration of GC is also elevated. Thus, we will also investigate whether the relationship between the meal-entrained cortisol secretion and leptin night rise is perturbed in upper body obese (UBO). UBO have a high risk of developing metabolic complications, and represent a subgroup of obese with the most well-characterized abnormalities of the HPA axis. We hypothesize that UBO will exhibit a more robust and homogenous response to cortisol manipulations than a random subset of obese individuals. Taken together, these experiments should provide information on basic mechanisms of nutritional/hormonal effects on serum leptin, as well as preliminary data on how these mechanisms may be altered in obesity. Ultimately, these results would lead to a better understanding of the mechanisms of leptin dysregulation in obese subjects [unreadable] [unreadable]